Project Summary/ Abstract Core cognitive functions involving memory are known to emerge as a result of coordination of activity at the level of neural populations across distributed networks in the brain. Although neural coordination is known to be involved in cognitive function, we lack a complete understanding of physiological mechanisms that mediate coordination and temporal patterns, and whether this coordination can be targeted at the systems-level to impact cognitive function. We aim to address this challenge by dissecting physiological mechanisms of long- range coordination in two key brain regions important for memory-guided behavior, the hippocampus and prefrontal cortex. We will use an associative memory task that utilizes odor-place associations in a spatial maze to investigate the role of rhythmic network oscillations and temporally patterned ensemble activity in coordinating the hippocampal-prefrontal network. We have found that multiple brain rhythms are prominent in these regions during recall, online maintenance, and formation of associative memories; and we will test the novel hypothesis that the same core memory networks are dynamically engaged by distinct rhythms for coordination during different memory processes. Further, we will directly manipulate this coordination using real-time feedback methods in loss- and gain-of-function experiments. We have established the relevant expertise to carry out this approach by combining high-density recordings during behavior with real-time detection of network patterns and closed-loop feedback using electrical and optogenetic stimulation. First, we will use multisite recording to simultaneously monitor ensemble activity in the hippocampus and prefrontal cortex, as well as activity in the olfactory bulb, in rats as they retrieve learned odor cue-place associations to guide behavioral choices for reward. We will investigate how distinct rhythms, namely beta oscillations (15-30 Hz) and theta oscillations (6-10 Hz), mediate coordination of these networks during memory recall and for online maintenance during working memory respectively. We will further determine how oscillation phase- entrained activity of hippocampal and prefrontal populations underlies communication to support these memory processes, and use decoding techniques to investigate how temporally coordinated ensemble activity mediates associative memories. Next, we will causally test the role of rhythmic patterns in memory using real-time detection and closed-loop feedback for optogenetically manipulating hippocampal-prefrontal coordination at specific phases of prevalent oscillations. In particular, we will test if perturbing or enhancing activity at preferred phases for communication disrupts or enhances memory function respectively. Finally, we will use these physiology and causal manipulation approaches to test the role of reactivation during sharp-wave ripples (150- 250 Hz) in formation of novel associations and driving coordination during learning. This proposal will thus provide crucial insight in the role of oscillatory network activity in hippocampal-prefrontal coordination for associative memory, and provide novel tools for impacting cognitive function by manipulating this coordination.